WO 95/10516, published Apr. 20, 1995 discloses tricyclic compounds useful for inhibiting farnesyl protein transferase.
In view of the current interest in inhibitors of farnesyl protein transferase, a welcome contribution to the art would be compounds useful for the inhibition of farnesyl protein transferase. Such a contribution is provided by this invention.
This invention provides compounds useful for the inhibition of farnesyl protein transferase (FPT). The compounds of this invention are represented by the formula: 
or a pharmaceutically acceptable salt or solvate thereof, wherein:
(A) a represents N or NOxe2x88x92;
(B) R1 and R3 are the same or different halo atom;
(C) R2 and R4 are selected from H and halo, provided that at least one of R2 and R4 is H;
(D) the dotted line (xe2x80x94 xe2x80x94 xe2x80x94) represents an optional bond;
(E) X is N, C when the optional bond to X is present, or CH when the optional bond to X is absent;
(F) m is 0, 1 or 2;
(G) a represents:
1. a cycloalkyl ring selected from: 
2. a heterocycloalkyl ring selected from: 
(H) p is 0, 1 or 2;
(I) when n or p is 1 then R5 is selected from:
(1) xe2x95x90O, with the proviso that when R is heterocycloalkyl Ring 10.0 and m is 0, 1 or 2 then the xe2x95x90O group is not bound to a carbon that is adjacent to the ring nitrogen, and with the proviso that when R is heterocycloalkyl Ring 11.0 and m is 1 or 2 then the xe2x95x90O group is not bound to a carbon that is adjacent to the ring nitrogen;
(2) xe2x95x90Nxe2x80x94OH;
(3) xe2x95x90Nxe2x80x94OR7 wherein R7 represents a C1 to C6 alkyl group;
(4) xe2x95x90Nxe2x80x94N(H)xe2x80x94C(O)xe2x80x94R8 wherein R8 represents xe2x80x94NH2 or C1 to C6 alkyl;
(5) xe2x95x90Nxe2x80x94Oxe2x80x94(CH2)rxe2x80x94C(O)xe2x80x94R11 wherein r is 1, 2, or 3, and R11 is selected from: xe2x80x94OH, xe2x80x94O-alkyl or xe2x80x94NH2;
(6) xe2x95x90Nxe2x80x94Oxe2x80x94(CH2)sxe2x80x94Oxe2x80x94R12, wherein s is 2, 3, or 4 and R12 is selected from: H, alkyl or trialkylsilyl (e.g., Si(CH3)2xe2x80x94C(CH3)3);
(7) xe2x80x94NR13R14 wherein R13 and R14 are independently selected from:
(a) H;
(b) acyl;
(c) alkyl;
(d) aralkyl;
(d) cycloalkyl;
(e) heterocycloalkyl;
(f) heteroaralkyl;
(g) xe2x80x94S(O)2R15 wherein R15 is C1 to C6 alkyl or aryl; or
(h) an aralkyl, cycloalkyl, heterocycloalkyl, heteroaryl or heteroaralkyl having from 1 to 3 substituents selected from: xe2x95x90O, halo, xe2x80x94OH or xe2x80x94O-alkyl, wherein said substiuents being bound to substitutable ring carbons; or
(8) OR16 wherein R16 is selected from:
(a) H;
(b) C1 to C6 alkyl;
(c) xe2x80x94C(O)R17 wherein R17 is selected from: alkyl, aryl, heteroaryl or aralkyl; or
(d) xe2x80x94C(O)NHR18 wherein R18 is selected from: H, xe2x80x94C(O)R19 wherein R19 is selected from: xe2x80x94C(Cl)3, alkyl or xe2x80x94(CH2)2OH;
(J) when n or p is 2, then each R5 is the same or different and each R5 is selected from:
(1) xe2x80x94NR13R14 wherein R13 and R14 are independently selected from:
(a) H;
(b) acyl;
(c) alkyl;
(d) aralkyl;
(d) cycloalkyl;
(e) heterocycloalkyl;
(f) heteroaralkyl;
(g) xe2x80x94S(O)2R15 wherein R15 is C1 to C6 alkyl or aryl; or
(h) an aralkyl, cycloalkyl, heterocycloalkyl, heteroaryl or heteroaralkyl having from 1 to 3 substituents selected from: xe2x95x90O, halo, xe2x80x94OH or xe2x80x94O-alkyl, wherein said substiuents being bound to substitutable ring carbons; or;
(2) OR16 wherein R16 is selected from:
(a) H;
(b) C1 to C6 alkyl;
(c) xe2x80x94C(O)R17 wherein R17 is selected from: alkyl, aryl, heteroaryl or aralkyl; or
(d) xe2x80x94C(O)NHR18 wherein R18 is selected from: H, xe2x80x94C(O)R19 wherein R19 is selected from: xe2x80x94C(Cl)3, alkyl or xe2x80x94(CH2)2OH; or
(K) provided that R1 is not bound to a carbon atom adjacent to the nitrogen atom in Rings 9.0, 10.0, 11.0 or 12.0;
(L) Y is selected from O or S, provided that each Y is the same;
(M) Z represents the remainder of cycloalkyl Rings 2.0, 3.0 or 4.0, such that spiro ring T is bound to one of the carbon atoms in said cycloalkyl ring;
(N) W represents the remainder of cycloalkyl Ring 5.0, such that spiro ring T is bound to one of the carbon atoms in said cycloalkyl ring;
(O) Q represents the remainder of heterocycloalkyl Rings 9.0, 10.0 or 11.0, such that spiro ring T is bound to one of the carbon atoms in said heterocycloalkyl ring, provided that spiro Ring T is not bound to a carbon atom adjacent to the nitrogen atom; and
(P) R6 is selected from: alkoxy, alkyl or xe2x80x94OH.
The compounds of this invention: (i) potently inhibit farnesyl protein transferase, but not geranylgeranyl protein transferase I, in vitro: (ii) block the phenotypic change induced by a form of transforming Ras which is a farnesyl acceptor but not by a form of transforming Ras engineered to be a geranylgeranyl acceptor; (iii) block intracellular processing of Ras which is a farnesyl acceptor but not of Ras engineered to be a geranylgeranyl acceptor; and (iv) block abnormal cell growth in culture induced by transforming Ras.
The compounds of this invention inhibit farnesyl protein transferase and the farnesylation of the oncogene protein Ras. Thus, this invention further provides a method of inhibiting farnesyl protein transferase, (e.g., ras farnesyl protein transferase) in mammals, especially humans, by the administration of an effective amount of the tricyclic compounds described above. The administration of the compounds of this invention to patients, to inhibit farnesyl protein transferase, is useful in the treatment of the cancers described below.
This invention provides a method for inhibiting or treating the abnormal growth of cells, including transformed cells, by administering an effective amount of a compound of this invention. Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) expressing an activated Ras oncogene; (2) tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene; and (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs.
This invention also provides a method for inhibiting or treating tumor growth by administering an effective amount of the tricyclic compounds, described herein, to a mammal (e.g., a human) in need of such treatment. In particular, this invention provides a method for inhibiting or treating the growth of tumors expressing an activated Ras oncogene by the administration of an effective amount of the above described compounds. Examples of tumors which may be inhibited or treated include, but are not limited to, lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma, breast cancer and prostate cancer.
It is believed that this invention also provides a method for inhibiting or treating proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genesxe2x80x94i.e., the Ras gene itself is not activated by mutation to an oncogenic formxe2x80x94with said inhibition or treatment being accomplished by the administration of an effective amount of the tricyclic compounds described herein, to a mammal (e.g., a human) in need of such treatment. For example, the benign proliferative disorder neurofibromatosis, or tumors in which Ras is activated due to mutation or overexpression of tyrosine kinase oncogenes (e.g., neu, src, abl, lck, and fyn), may be inhibited or treated by the tricyclic compounds described herein.
The tricyclic compounds useful in the methods of this invention inhibit or treat the abnormal growth of cells. Without wishing to be bound by theory, it is believed that these compounds may function through the inhibition of G-protein function, such as ras p21, by blocking G-protein isoprenylation, thus making them useful in the treatment of proliferative diseases such as tumor growth and cancer. Without wishing to be bound by theory, it is believed that these compounds inhibit ras farnesyl protein transferase, and thus show antiproliferative activity against ras transformed cells.
As used herein, the following terms are used as defined below unless otherwise indicated:
BOC-represents tert-butyloxycarbonyl;
CBZ-represents benzyloxycarbonyl;
Et (or ET)-represents ethyl (C2H5);
MH+-represents the molecular ion plus hydrogen of the molecule in the mass spectrum;
acyl-represents a Gxe2x80x94C(O)xe2x80x94 group wherein G represents alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, xe2x80x94O-alkyl, xe2x80x94O-aryl, or NR100R200 wherein R100 and R200 are independently selected from alkyl or aryl;
alkyl-represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably one to six carbon atoms;
aralkyl-represents an alkyl group, as defined above, substituted with an aryl, as defined below, such that the bond from another substituent is to the alkyl moiety;
aryl-(including the aryl portion of aryloxy and aralkyl)-represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring (e.g., aryl is a phenyl ring), with all available substitutable carbon atoms of the carbocyclic group being intended as possible points of attachment, said carbocyclic group being optionally substituted (e.g., 1 to 3) with one or more of halo, alkyl, hydroxy, alkoxy, phenoxy, CF3, amino, alkylamino, dialkylamino, xe2x80x94COOR300 or xe2x80x94NO2, wherein R300 represents alkyl or aryl; and
cycloalkyl-represents saturated carbocyclic rings branched or unbranched of from 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms;
halo-represents fluoro, chloro, bromo and iodo;
heteroaralkyl-represents and alkyl group, as defined above, substitued with a heteroaryl group, as defined below, such that the bond from another substituent is to the alkyl moiety;
heteroaryl-represents cyclic groups, optionally substituted with R3 and R4, having at least one heteroatom selected from O, S or N, said heteroatom interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the aromatic heterocyclic groups preferably containing from 2 to 14 carbon atoms. e.g., triazolyl, 2-, 3- or 4-pyridyl or pyridyl N-oxide (optionally substituted with R3 and R4), wherein pyridyl N-oxide can be represented as: 
heterocycloalkyl-represents a saturated, branched or unbranched carbocylic ring containing from 3 to 15 carbon atoms, preferably from 4 to 6 carbon atoms, which carbocyclic ring is interrupted by 1 to 3 hetero groups selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NR400, wherein R400 represents alkyl, aryl or acyl-(suitable heterocycloalkyl groups including 2- or 3-tetrahydrofuranyl, 2- or 3-tetrahydrothienyl, 2-, 3- or 4-piperidinyl, 2- or 3-pyrrolidinyl, 2- or 3-piperizinyl, 2- or 4-dioxanyl, etc.).
The following solvents and reagents are referred to herein by the abbreviations indicated: ethanol (EtOH); methanol (MeOH); acetic acid (HOAc or AcOH); ethyl acetate (EtOAc); N,N-dimethylformamide (DMF); trifluoroacetic acid (TFA); trifluoroacetic anhydride (TFAA); 1-hydroxybenzotriazole (HOBT); 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (DEC); diisobutylaluminum hydride(DIBAL); and 4-methylmorpholine (NMM).
The positions in the tricyclic ring system are: 
Preferred halo atoms for R1, R2, R3, and R4 in Formula 1.0 are selected from: Br, Cl or I, with Br and Cl being preferred.
Compounds of Formula 1.0 include compounds of Formulas 1.1 and 1.2: 
wherein R1, R3 and R4 in Formula 1.1 are halo, and R1, R2 and R3 in Formula 1.2 are halo. Compounds of Formula 1.1 are preferred.
Preferably, in Formula 1.1, R1 is Br, R 3 is Cl, and R4 is halo. More preferably, in Formula 1.1, R1 is Br, R3 is Cl, and R4 is Br.
Preferably, in Formula 1.2, R1 is Br, R2 is halo, and R3 is Cl. More preferably, in Formula 1.2, R1 is Br, R2 is Br, and R3 is Cl.
Preferably, for compounds of Formulas 1.1 and 1.2, X is CH or N. For compounds of Formula 1.1, X is preferably CH.
Preferably, for the compounds of this invention, the optional bond between positions 5 and 6 (i.e., C5-C6) in the tricyclic system is absent.
Also, preferably, for the compounds of this invention, substituent a in Ring I represents N.
Those skilled in the art will appreciate that compounds of Formula 1.0 include compounds of Formulas 1.3 and 1.4: 
wherein X is CH or N, with compounds of 1.3 being preferred for compounds of Formula 1.1, and with compounds of Formula 1.4 being preferred for compounds of Formula 1.2.
Thus, compounds of the invention include compounds of the formulas: 
Compounds of Formula 1.9 are preferred.
Preferred cycloalkyl rings for substituent R are: 
More preferred cycloalkyl rings for substituent R are: 
Most preferred cycloalkyl rings for substituent R is: 
Preferably, the optional bond is absent in Formulas 2.0, 3.0, 4.0, 6.0 and 7.0. Also, preferably, for Ring 6.0, R6 is xe2x80x94OCH3.
Preferably, spiro Ring 7.0 is 
Most preferably, spiro Ring 7.0 is: 
Preferred heterocycloalkyl rings for substituent R are 
Preferably p is 0.
Preferably, R is a cycloalkyl ring, and more preferably R is cycloalkyl Ring 4.0. Preferably, when n is 1, R5 is at the 4-position, i.e, preferably R is: 
When R is a heterocycloalkyl ring, and when n is 1, then R5 is preferably at the 4-position, i.e., R is 
Preferably, when n is 1, R5 is selected from: xe2x95x90O, xe2x95x90Nxe2x80x94OH, xe2x95x90Nxe2x80x94OCH3, xe2x95x90Nxe2x80x94NHxe2x80x94C(O)xe2x80x94NH2, xe2x95x90Nxe2x80x94NHxe2x80x94C(O)xe2x80x94CH3, xe2x95x90Nxe2x80x94Oxe2x80x94CH2xe2x80x94C(O)xe2x80x94OH, xe2x95x90Nxe2x80x94Oxe2x80x94(CH2)2xe2x80x94Oxe2x80x94Si(CH3)2-C(CH3)3, xe2x80x94NHSO2CH3, xe2x80x94NH2, xe2x80x94NHC(O)C(O)OC2H5, xe2x80x94NHC(O)NH2, xe2x80x94NHC(O)OC(CH3)3, xe2x80x94NHC(O)C(O)NH2, xe2x80x94OC(O)CH3, or xe2x80x94OH.
More preferably, when n is 1, R5 is selected from: xe2x95x90O, xe2x95x90Nxe2x80x94OH, xe2x95x90Nxe2x80x94OCH3, xe2x95x90Nxe2x80x94NHxe2x80x94C(O)xe2x80x94NH2, xe2x95x90Nxe2x80x94NHxe2x80x94C(O)xe2x80x94CH3, xe2x95x90Nxe2x80x94Oxe2x80x94CH2xe2x80x94C(O)xe2x80x94OH, or xe2x80x94OC(O)CH3.
Those skilled in the art will recognize that the representative compounds listed below also serve to illustrate representative substituents for R, and hence R5 in Formula 1.0.
Representative compounds of the invention include: 
Compounds of Formula 1.0 include compounds of the formula: 
wherein R20 is selected from the substituents listed in Table 1:
Compounds of Formula 1.0 also include compounds of the formula: 
wherein R21 is selected from the substituents listed in Table 2:
Compounds of Formula 1.0 also include compounds of the formula: 
wherein R22 is selected from the substituents in Table 3:
Compounds of formula 1.0 also include compounds of the formula: 
Compounds of Formula 1.0 also include compounds of the formula: 
wherein R23 is selected from the substituents in Table 4:
Lines drawn into the ring systems indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms.
Certain compounds of the invention may exist in different isomeric (e.g., enantiomers, diastereoisomers, atropisomers) forms. The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures. Enol forms are also included.
Certain tricyclic compounds will be acidic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
Certain basic tricyclic compounds also form pharmaceutically acceptable salts, e.g., acid addition salts. For example, the pyrido-nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the invention.
All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
Compounds of the invention may be prepared according to the procedures described in WO 95/10516 published Apr. 20, 1995, U.S. Pat. No. 5,719,148 issued Feb. 17, 1998, and copending application Ser. No. 08/766,601 filed Dec. 12, 1996; the disclosures of each being incorporated herein by reference thereto; and according to the procedures described below.
Compounds of the invention can be prepared according to the reaction: 
In the reaction, the keto acid, ketal acid, oxime acid or hydrazone carboxylic acid (118.0) is coupled to the tricyclic amine (117.0) using amide bond forming conditions well known to those skilled in the art. The substituents are as defined for Formula 1.0. For example, carbodiimide coupling methods (e.g., DEC) can be used. For example, the carboxylic acid (118.0) can be reacted with the tricyclic amine (117.0) using DEC/HOBT/-NMM in DMF at about 25xc2x0 C. for a sufficient period of time. e.g., about 18 hours, to produce a compound of Formula 1.0.
For example, using the carbodiimide coupling methods, compounds of the invention can be produced according to the reaction: 
The keto acids, ketal acids, oxime acids or hydrazone acids (118.0) are either commercially available or can be prepared by methods well known in the art. In many cases the corresponding ketoesters, ketal esters, oxime esters or hydrazone esters, which can be hydrolyzed to the corresponding acids, are either commercially available or can be prepared by methods well known in the art. The keto, ketal, oxime and hydrazone groups in the intermediate (118.0), or in the product (1.22) can be interconverted by methods well known in the art.
Compounds of Formula 1.0 wherein m is 0 and R is 
can be prepared by reaction of the corresponding carboxylic acid: 
with a tricyclic amine of Formula 117.0. Carboxylic acids 122.0 and 123.0 can be prepared according to the procedure described in J. Med. Chem. 1993 36, 1100. The N atom of 122.0 and 123.0 can be protected with a suitable protecting group. e.g., t-butoxycarbonyl (BOC), by techniques well known to those skilled in the art to provide intermediate acids 124.0 or 125.0: 
The tricyclic amine of Formula 117.0 (e.g., Formula 119.0), is reacted with the N-protected 4-aminocyclohexanecarboxylic acid (124.0 or 125.0), a dehydrating agent (e.g., 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (DEC.HCl)), a catalyst (e.g., 1-hydroxy-benzotriazole hydrate (HOBT.H2O )) and a base (e.g., N-methyl-morpholine (NMM)) in a suitable solvent (e.g., DMF) to give a compound of Formula 1.0.
For example, 
The BOC group (xe2x80x94C(O)O-t-Bu) can be removed by techniques known in the art to obtain another compound of the invention. For example, reaction of Formula 36.0 with trifluoroacetic acid (TFA) in a suitable solvent, e.g., CH2Cl2, provides a compound of Formula 37.0: 
The compound of Formula 37.0 can be derivatized by reaction with different reagents using techniques well know in the art to give additional compounds of the invention, i.e., compounds of Formula 1.17a. Such reagents and conditions, and the compound that is produced are summarized in Table 5. R20 in Table 5 refers to the substituent in Formula 1.17a 
and the compound numbers in parenthesis in the column for R20 refer to the compounds described above.
The corresponding trans compounds can be prepared following the above procedure with Formula 125.0.
Compounds of Formula 1.0, wherein m is 0 and R is: 
for example 
can be prepared by reaction of 117.0 (e.g., 119.0) with the corresponding carboxylic acid 
The carboxylic acid, 130.0, can be prepared according to techniques known in the art (e.g., J. Am. Chem. Soc. 1938, 60, 2341). The nitrogen atom of cis-(+/xe2x88x92)-3-aminocyclohexanecarboxylic acid 130.0 can be protected with a suitable protecting group (e.g., BOC) by techniques known in the art to provide intermediate acid 131.0: 
Following the procedures described above for the 1,4-cyclohexyl derivatives, the 1,3-cyclohexyl derivatives can be made from 131.0 and 117.0. Thus, for example, reaction of 126.0 with 131.0 provides Compound 43.0. Reaction of 43.0 with TFA yields Compound 44.0. Additional compounds of the invention are produced from Compound 1.18 
and the reagents listed in Table 6:
Similar to the procedures described above, enantiomerically pure cis-3-aminocyclohexanecarboxylic acid (Aust. J. Chem. 1981, 34, 2231) having 1R,3S (132.0) or 1S,3R (133.0) absolute configuration 
could be used to prepare compounds of Formula 1.0 that are similar to the compounds of Formulas 43.0 and 44.0 and their derivatives described above.
Compounds similar to 43.0 and 44.0, and their derivatives described above, can be prepared from (+/xe2x88x92)-trans-3-aminocyclohexanecarboxylic acid {(+/xe2x88x92)-134.0}
(J. Org. Chem. 1949, 14, 1013) by the methodology described above. Those skilled in the art will recognize that {(+/xe2x88x92)-134.0} can be resolved into individual enantiomers 135.0 and 136.0 
by using any of several standard techniques, e.g., chromatography of the acid or a suitable derivative on a xe2x80x9cchiralxe2x80x9d column; fractional crystallization of a diastereomerically enriched salt, e.g. brucine, strychnine, ornithine; preparation of a derivative using an enantiomerically pure reagent, e.g., (+)-menthyl chloroformate; or enzymatic resolution of an appropriate derivative, e.g. porcine pancreatic lipase hydrolysis of an ester, e.g. the ethyl ester. Compounds similar to 43.0 and 44.0 and their derivatives described above can be prepared from enantiomiers 135.0 and 136.0 by the methodology described above.
Compounds of Formula 1.0, wherein m is 1 and R is 
can be prepared by reaction of the corresponding N-protected (e.g., BOC) carboxylic acid: 
with the tricyclic amine 117.0. The N-protected 139.0 and 140.0 (Chem. Ber. 1934, 67, 245) can be prepared using techniques known in the art. From these compounds and a tricyclic amine 117.0, e.g., 119.0, Compounds 50.0, 51.0, 52.0 and 53.0 (described above) can be obtained. Derivatives of Compounds 51.0 and 53.0 can be prepared by procedures similar to those described above. Reagents and conditions for the preparation of Compounds of Formulas 1.19 and 1.20 
i.e., Compounds 54.0-57.0, are given in Table 7:
Compounds of Formula 1.0, wherein m is 1 and R is 
such as, for example, 
can be prepared by reaction of the corresponding carboxylic acid 
with a tricyclic amine 117.0. Carboxylic acids (+/xe2x88x92)-cis 144.0 and (+/xe2x88x92)-trans 145.0 can be prepared according to the procedure described in J. Org. Chem. 1949, 14, 1013. Each of these acids may be protected on nitrogen with, e.g., BOC, to give (+/xe2x88x92)-146.0 and (+/xe2x88x92)-147.0 
The N-protected acids (146.0 or 147.0) are reacted with a tricyclic amine 117.0, e.g., 119.0 (e.g., 126.0), according to the procedures discussed above (see for example the preparation of Compound 37.0). In this manner, Compounds 64.0 and 65.0, described above, can be prepared. Compounds 64.0 and 65.0 can be derivatized to produce compounds according to the procedure described above for the preparation of Compounds 58.0 to 63.0.
Those skilled in the art will recognize that (+/xe2x88x92)-146.0 and (+/xe2x88x92)-147.0 can be resolved into individual enantiomers by using any of several standard techniques, e.g., chromatography of the acid or a suitable derivative on a xe2x80x9cchiralxe2x80x9d column; fractional crystallization of a diastereomerically enriched salt, e.g. brucine, strychnine, or ornithine, preparation of a derivative using an enantiomerically pure reagent, e.g., (+)-menthyl chloroformate; or enzymatic resolution of an appropriate derivative, e.g., porcine pancreatic lipase hydrolysis of an ester, e.g., the ethyl ester. Further, nitrogen protected derivatives, e.g., BOC, of the individual enantiomers of cis- and trans-3-aminocyclohexylacetic acid, can be prepared using standard techniques known to those skilled in the art to provide intermediates 148.0, 149.0, 150.0 and 151.0 having the absolute stereochemistries drawn: 
Compounds 148.0-151.0 can be reacted with a tricyclic amine of Formula 117.0, e.g., 126.0, according to the procedures described above, to produce compounds 64.0, 65.0, 66.0 and 67.0. Compounds 64.0-67.0 can be derivatized to produce compounds according to the procedure described above for the preparation of Compounds 58.0 to 63.0.
Compounds of Formula 1.0 wherein m is 0 and R is 
can be made by reacting the corresponding carboxylic acid with a tricyclic amine of Formula 117.0, e.g., 126.0.
Trans-4-hydroxycyclohexanecarboxylic acid (153.0) 
can be treated with, for example, 126.0, a dehydrating agent (e.g., DEC.HCl); a catalyst (e.g., HOBT.H2O); and a base (e.g., NMM) in a suitable solvent (e.g., DMF) to give Compound 68.0.
Cis-4-hydroxycyclohexanecarboxylic acid (154.0) 
can be treated with an acid anhydride (e.g., acetic anhydride) and a base(e.g., pyridine) to afford cis-4-acetoxycyclohexanecarboxylic acid (155.0) 
Compound 155.0 can be coupled with a tricyclic amine of formula 117.0, e.g., 126.0, using the procedures described above for the preparation of 68.0, to afford Compound 69.0. Compound 69.0 can be treated with an acid (e.g., 6 M HCl) to afford Compound 70.0.
Similar to the procedure described above for the 4-hydroxycyclohexyl derivatives, compounds of Formula 1.0 wherein m is 0 and R is 
can be prepared. Thus, by reacting 126.0 with the acids 
Compounds 71.0, 72.0, 73.0, 74.0, 75.0 and 76.0, respectively can be obtained.
Compounds of Formula 1.0 wherein m is 0 and R is 
can be prepared by reacting a tricyclic amine of Formula 117.0, e.g., 126.0, with the corresponding carboxylic acid of 163.0 or 164.0 using to the procedures described above for preparing Compounds 68.0 and 70.0. Compounds 77.0 or 78.0 are prepared in this manner.
Compounds of Formula 1.0 wherein m is 0 and R is a cyclohexyl ring having an alkoxy substituent (e.g., methoxy)xe2x80x94see compounds 79.0 to 86.0xe2x80x94can be prepared from the corresponding carboxylic acid of the alkoxy substitued cyclohexyl ring by the procedures described above.
Compounds of Formula 1.0 wherein m is 0 and R is a cyclohexyl ring having an ester substituent (e.g., Compound 87.0) can be prepared by techniques known in the art from compounds having a hydroxy substitued cyclohexyl ring. For example, compound 87.0 can be prepared by treating Compound 68.0 with benzoyl chloride an acid chloride (an acid chloride) and pyridine (a base) in dichloromethane (solvent).
Compounds of Formula 1.0 wherein m is 1 and R is a cyclohexyl ring substitued with a carbamate can be prepared from a corresponding compound that is a monoalcohol (i.e., R is a hydroxy substitued cyclohexyl ring). The carbamates can be prepared by techniques well known in the art, such as reaction with an isocyanate in a suitable base and a suitable solvent. For example, Compound 68.0 can be reacted with trichloroacetyl isocyanate and pyridine (base) in dichloromethane (solvent) to yield Compound 88.0. the trichloroacetyl group can be hydrolyzed to yield Compound 89.0. Hydrolysis can be done with K2CO3 in methanol.
Additionally, any of the alcohols mentioned above could be reacted with a chloroformate, e.g., 4-nitrophenyl chloroformate, and a base, e.g., Et3N, to give carbonate 90.0. Treatment of 90.0 with any primary or secondary amine, e.g., ethanolamine, would afford a carbamate, e.g., 91.0.
(+/xe2x88x92)-4-Ethoxy-3-hydroxycyclohexanecarboxylic acid (J. Org. Chem.; 1961, 26, 1405) can be coupled with a tricyclic amine of Formula 117.0, e.g., 126.0, using the procedures described above for the preparation of 68.0 and 70.0 to afford Compound 92.0 as a mixture of diastereomers. Similarly, a tricyclic amine, such as 126.0, can be coupled with (+/xe2x88x92)-4-hydroxy-3-methoxycyclohexanecarboxylic acid (J. Org. Chem.; 1992, 57, 1405) to afford compound 93.0 as a mixture of diastereomers. One of the tricyclic amines, such as 126.0, can be coupled with (+/xe2x88x92)-4,3-dimethoxycyclohexanecarboxylic acid to afford Compound 94.0 as a mixture of diastereomers. Treatment of one of the monoalcohols, e.g., 92.0, with an alkyl halide, e.g., benzyl bromide, a base, e.g., NaH, in a solvent, e.g., DMF would afford 3-benzyl-4-ethyl diether 95.0 as a mixture of diastereomers.
Epoxyester 165.0 (Tetrahedron, 1992, 48, 539) could be treated with an alcohol, e.g., benzyl alcohol, and a base, e.g., NaH, in a suitable solvent, e.g., THF, to afford a mixture of esters 166.0 and 167.0: 
Hydrolysis of the esters and coupling of the resultant acids with a tricyclic amine of Formula 117.0, e.g., 126.0, using the procedures described above for the preparation of 68.0 and 70.0. yields compounds of the invention illustrated by Compound 96.0.
Compound 77.0 could be treated with an acid chloride, e.g., acetyl chloride, or a chemically equivalent reagent, and a base, e.g., pyridine, in a suitable solvent, e.g., dichloromethane, to obtain esterified compounds exemplified by diacetate Compound 97.0.
Acid 168.0, derived from ester 166.0 (described above), could be treated with two equivalents of a base, e.g., NaH, and one equivalent of a silyl chloride, e.g., t-butyldiphenylchlorosilane, in a suitable solvent, e.g., DMF, to afford acid 169.0 
The benzyl group could be removed, e.g., by catalytic hydrogenation, and the resulting hydroxy acid 170.0 could be coupled with a tricyclic amine, e.g. 126.0, using the procedures described above for the preparation of 68.0 and 70.0, to afford the Compound 171.0 
Alcohol 171.0 could be treated with an acid chloride, e.g., acetyl chloride or an equivalent reagent, and a base, e.g., pyridine, in a solvent, e.g., dichloromethane, to afford acetate 172.0 
Removal of the silyl group by any of the methods known in the art would give hydroxyacetate 98.0A. Following a similar procedure starting with the acid derived from 167.0 would provide 98.0B 
The hydroxyacetates 98.0A and 98.0B could be treated with an acid chloride, e.g., benzoyl chloride or an equivalent reagent, and a base, e.g., pyridine, in a solvent, e.g., dichloromethane, to afford diesters 99.0A and 99.0B, respectively 
Any of the monoethers described above, e.g., 92.0, could be treated with an acid chloride, e.g., acetyl chloride, or a chemically equivalent reagent, and a base, e.g., pyridine, in a suitable solvent, e.g., dichloromethane, to obtain esterified compounds exemplified by acetate Compound 100.0.
Starting from any of the monoalcohols or diols described above, and following the procedure outlined above for the preparation of 88.0, 89.0 and 91.0, carbamates exemplified by Compounds 101.0, 102.0 and 103.0 could be prepared.
(+/xe2x88x92)-3,5-Dimethoxycyclohexanecarboxylic acid (German Patent DE 81443) can be coupled with a tricyclic amine of formula 117.0, e.g., 126.0, using the procedures described above for the preparation of 68.0 and 70.0 to afford Compound 104.0 as a mixture of diastereomers.
Racemic ester 173.0 (J. Am. Chem. Soc. 1994, 116, 3296) could be hydrolyzed to the acid 174.0 
and 174.0 can be coupled with e.g., 126.0 (a tricyclic amine of 117.0) using the procedures described above for the preparation of 68.0 and 70.0 to afford Compound 105.0 as a mixture of diastereomers. Removal of the silyl group by methods known in the art would give hydroxyether 106.0. Treatment of 106.0 with an alkyl halide, e.g., benzyl bromide, a base, e.g., NaH, in a solvent, e.g., DMF would afford 3-benzyl-5-methyl ether 107.0 as a mixture of diastereomers.
Hydroxy Compound 78.0 could be treated with an acid chloride, e.g., acetyl chloride, or a chemically equivalent reagent, and a base, e.g., pyridine, in a suitable solvent, e.g., dichloromethane, to obtain an esterified target exemplified by diacetate 108.0.
Racemic hydroxyester 175.0 (J. Am. Chem. Soc. 1994, 116, 3296) could be hydrolyzed to the acid 176.0 
and 176.0 could be coupled with a tricyclic amine (117.0), e.g., 126.0, using the procedure described above for the preparation of 68.0 and 70.0 to afford Compound 109.0. Alcohol 109.0 could be treated with an acid chloride, e.g., acetyl chloride or an equivalent reagent, and a base, e.g., pyridine, in a solvent, e.g., dichloromethane, to afford acetate 110.0. Removal of the silyl group by methods known in the art would give hydroxyacetate 111.0. Hydroxyacetate 111.0 could be reacted with an acid chloride, e.g., benzoyl chloride, and a base, e.g., pyridine, in a suitable solvent, e.g., dichloromethane to afford diester 112.0.
A monoether e.g., 106.0, could be reacted with an acid chloride, e.g., acetyl chloride, or a chemically equivalent reagent, a base, e.g., pyridine, in a suitable solvent, e.g., dichloromethane, to obtain compounds exemplified by Compound 113.0.
Starting from any of the monoalcohols or diols described above, and following the procedures outlined above for the preparation of 88.0, 89.0 and 91.0, carbamates exemplified by Compounds 114.0, 115.0 and 116.0 can be obtained.
Cyclic ketones (177.0) can be alkylated next to the carbonyl with a bromo ester (178.0) under basic conditions as described in J. Am. Chem. Soc. (1957), 79, 3503. The corresponding ketoesters (179.0) are easily hydrolyzed with aqueous base to give the keto acids (180.0) 
wherein Ring V represents a 4, 5 or 6 membered cycloalkyl ring defined above, and wherein m is as defined for Formula 1.0 above.
Cyclic ketoamines can be alkylated in the nitrogen with a bromoester and then hydrolyzed as described in J. Med. Chem. (1994), 37, 3883 
wherein Ring D represents a 4, 5 or 6 membered heterocycloalkyl ring, as defined above, (inclusive of the heteroatom N), wherein the xe2x95x90O substituent is not on a carbon adjacent to the N atom, and wherein m is as defined for Formula 1.0 above.
Monoprotected diketones can be reacted in a Wittig reaction followed by hydrolysis to the unsaturated keto acid, or by first reducing the double bond followed by hydrolysis to the saturated keto acid. Examples of this can be found in Tetrahedron (1995), 51, 10259, Synthetic Comm. (1990), 20, 2019, Chemical Abstracts (1958), 6370a and Chemical Abstracts (1957), 6371b. 
wherein Ring E represents a 4, 5, or 6 membered cycloalkyl ring defined above.
The ester in the above ketalesters can also be selectively hydrolyzed to the corresponding ketal acids which can be coupled to the tricyclic amine 119.0 to produce compounds of Formula 1.22 containing a ketal group 
are prepared by methods known in the art, for example by methods disclosed in WO 95/10516, in U.S. Pat. No. 5,131,423 and those described below. Compounds of Formula 13.0a wherein X is C (when the double bond is present) or CH and the C-3 postion of the pyridine ring in the tricyclic structure is substituted by bromo (i.e., R1 is Br) can also be prepared by a procedure comprising the following steps:
(a) reacting an amide of the formula 
wherein R11a is Br, R5a is hydrogen and R6a is C1-C6 alkyl, aryl or heteroaryl; R5a is C1-C6 alkyl, aryl or heteroaryl and R6a is hydrogen; R5a and R6a are independently selected from the group consisting of C1-C6 alkyl and aryl; or R5a and R6a, together with the nitrogen to which they are attached, form a ring comprising 4 to 6 carbon atoms or comprising 3 to 5 carbon atoms and one hetero moiety selected from the group consisting of xe2x80x94Oxe2x80x94 and xe2x80x94NR9axe2x80x94, wherein R9a is H, C1-C6 alkyl or phenyl;
with a compound of the formula 
wherein R1a, R2a, R3a and R4a are independently selected from the group consisting of hydrogen and halo and R7a is Cl or Br, in the presence of a strong base to obtain a compound of the formula 
(b) reacting a compound of step (a) with
(i) POCl3 to obtain a cyano compound of the formula 
(ii) DIBALH to obtain an aldehyde of the formula 
(c) reacting the cyano compound or the aldehyde with a piperidine derivative of the formula 
wherein L is a leaving group selected from the group consisting of Cl and Br, to obtain a ketone or an alcohol of the formula below, respectively: 
(d)(i) cyclizing the ketone with CF3SO3H to obtain a compound of the formula 
wherein the dotted line represents a double bond; or
(d)(ii) cyclizing the alcohol with polyphosphoric acid to obtain a compound wherein the dotted line represents a single bond.
Methods for preparing intermediate compounds disclosed in WO 95/10516, U.S. Pat. No. 5,151,423 and described below employ a tricyclic ketone intermediate. Such intermediates of the formula 
wherein R11b, R1a, R2a, R3a and R4a are independently selected from the group consisting of hydrogen and halo, can be prepared by the following process comprising:
(a) reacting a compound of the formula 
(i) with an amine of the formula NHR5aR6a, wherein R5a and R6a are as defined in the process above; in the presence of a palladium catalyst and carbon monoxide to obtain an amide of the formula: 
(ii) with an alcohol of the formula R10aOH, wherein R10a is C1-C6 lower alkyl or C3-C6 cycloalkyl, in the presence of a palladium catalyst and carbon monoxide to obtain the ester of the formula 
followed by reacting the ester with an amine of formula NHR5aR6a to obtain the amide;
(1b) reacting the amide with an iodo-substituted benzyl compound of the formula 
wherein R1a, R2a, R3a, R4a and R7a are as defined above, in the presence of a strong base to obtain a compound of the formula 
(c) cyclizing a compound of step (b) with a reagent of the formula R8aMgL, wherein R8a is C1-C8 alkyl, aryl or heteroaryl and L is Br or Cl, provided that prior to cyclization, compounds wherein R5a or R6a is hydrogen are reacted with a suitable N-protecting group.
Compounds of Formula 1.0, wherein substituent a is NO (Ring I) and X is C or CH, can be made from compounds of Formula 117.0A using procedures well known to those skilled in the art. For example the compound of Formula 117.0A can be reacted with m-chloro-peroxybenzoic acid in a suitable organic solvent, e.g., dichloro-methane (usually anhydrous) or methylene chloride, at a suitable temperature, to produce a compound of Formula 117.0B 
Generally, the organic solvent solution of Formula 117.0A is cooled to about 0xc2x0 C. before the m-chloroperoxybenzoic acid is added. The reaction is then allowed to warm to room temperature during the reaction period. The desired product can be recovered by standard separation means. For example, the reaction mixture can be washed with an aqueous solution of a suitable base, e.g., saturated sodium bicarbonate or NaOH (e.g., 1N NaOH), and then dried over anhydrous magnesium sulfate. The solution containing the product can be concentrated in vacuo. The product can be purified by standard means, e.g., by chromatography using silica gel (e.g., flash column chromatography).
Alternatively, compounds of Formula 1.0, wherein substituent a is NO and X is C or CH, can be made from compounds of Formula 1.0, wherein substituent a is N, by the m-chloroperoxybenzoic acid oxidation procedure described above.
Also, alternatively, the compounds of Formula 1.0, wherein substituent a is NO and X is C or CH, can be made from tricyclic ketone compounds 
using the oxidation procedure with m-chloroperoxybenzoic acid. The oxidized intermediate compounds 
are then reacted by methods known in the art to produce compounds of the invention.
Those skilled in the art will appreciate that the oxidation reaction can be conducted on racemic mixtures and the isomers can then be separated by know techniques, or the isomers can be separated first and then oxidized to the corresponding N-oxide.
Those skilled in the art will appreciate that it is preferable to avoid an excess of m-chloroperoxybenzoic acid when the oxidation reaction is carried out on the compounds having a C-11 double bond to piperidine Ring IV. In these reactions an excess of m-chloroperoxybenzoic acid can cause epoxidation of the C-11 double bond.
(+)-Isomers of compounds of Formula 117.0A wherein X is CH can be prepared with high enantioselectivity by using a process comprising enzyme catalyzed transesterification. Preferably, a racemic compound of Formula 117.0A, wherein X is C, the double bond is present and R4 is not H, is reacted with an enzyme, such as Toyobo LIP-300, and an acylating agent, such as trifluoroethly isobutyrate; the resultant (+)-amide is then hydrolyzed, for example by refluxing with an acid such as H2SO4, to obtain the corresponding optically enriched (+)-isomer wherein X is CH and R4 is not H. Alternatively, a racemic compound of Formula 117.0A. wherein X is C, the double bond is present and R4 is not H, is first reduced to the corresponding racemic compound of Formula 117.0A wherein X is CH and then treated with the enzyme (Toyobo LIP-300) and acylating agent as described above to obtain the (+)-amide, which is hydrolyzed to obtain the optically enriched (+)-isomer.
Compounds of the invention, wherein a is NO and X is N, can be prepared from the tricyclic ketone (II) described above. Ketone (II) can be converted to the corresponding C-11 hydroxy compound which in turn can be converted to the corresponding C-11 chloro compound 
and (IV) can then be reacted with piperazine to produce the intermediate 
Intermediate (V) can then be reacted with the reagents, using techniques well known in the art, which will provide the desired compound.
Compounds useful in this invention are exemplified by the following examples, which should not be construed to limit the scope of the disclosure.